Functional and behavioral effects of de novo mutations in calcium-related genes in patients with bipolar disorder.
Functional and behavioral effects of de novo mutations in calcium-related genes in patients with bipolar disorder.
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DOI：
10.1093/hmg/ddab152
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发表时间：
2021-09-15
影响因子：
3.5
通讯作者：
Kato T
中科院分区：
文献类型：
--
作者：
Nakamura T;Nakajima K;Kobayashi Y;Itohara S;Kasahara T;Tsuboi T;Kato T
双相情感障碍是一种常见的精神疾病，发生在大约1%的人中，需要终身治疗。虽然已知遗传因素导致了这种疾病，但遗传结构尚未完全阐明。我们最初对双相情感障碍进行的基于三个外显子的外显子组测序研究显示，在双相I型和分裂情感障碍合并的组中，新发突变、功能丧失(LOF)或蛋白改变突变丰富，所识别的新发突变富含钙相关基因。这些发现表明从头基因突变在双相情感障碍中起作用。如果确定突变对细胞功能和行为的功能影响，这些统计关联的有效性将得到加强。在这项研究中，我们重点研究了在双相情感障碍患者中发现的钙相关基因EHD1和MACF1的两个新的LOF突变。我们首先证明了EHD1突变导致了一种截短的蛋白质，对轴突生长的影响减弱，并抑制了内吞作用。接下来，我们使用CRISPR/Cas9建立了两个敲入小鼠系来模拟这些突变的体内效应。我们使用IntelliCage和长期车轮运行分析进行了行为筛查。Ehd1突变小鼠在光期表现出较高的活性。Macf1突变小鼠对奖励的注意力和坚持性降低。这些行为改变与之前提出的双相情感障碍动物模型的表型相似。这些发现支持从头基因突变作为双相情感障碍遗传结构的一个组成部分的可能作用，这是统计证据所表明的。
Bipolar disorder is a common mental illness occurring in approximately 1% of individuals and requires lifelong treatment. Although genetic factors are known to contribute to this disorder, the genetic architecture has not yet been completely clarified. Our initial trio-based exome sequencing study of bipolar disorder showed enrichment of de novo, loss-of-function (LOF) or protein-altering mutations in a combined group with bipolar I and schizoaffective disorders, and the identified de novo mutations were enriched in calcium-related genes. These findings suggested a role for de novo mutations in bipolar disorder. The validity of these statistical associations will be strengthened if the functional impact of the mutations on cellular function and behavior are identified. In this study, we focused on two de novo LOF mutations in calcium-related genes, EHD1 and MACF1, found in patients with bipolar disorder. We first showed that the EHD1 mutation resulted in a truncated protein with diminished effect on neurite outgrowth and inhibited endocytosis. Next, we used CRISPR/Cas9 to establish two knock-in mouse lines to model the in vivo effects of these mutations. We performed behavioral screening using IntelliCage and long-term wheel running analysis. Ehd1 mutant mice showed higher activity in the light phase. Macf1 mutant mice showed diminished attention and persistence to rewards. These behavioral alterations were similar to the phenotypes in previously proposed animal models of bipolar disorder. These findings endorse the possible role of de novo mutations as a component of the genetic architecture of bipolar disorder, which was suggested by the statistical evidence.
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影响因子：
4.6
作者：
Nakamura T;Nakajima K;Ohnishi T;Yoshikawa T;Nakanishi M;Takumi T;Tsuboi T;Kato T
通讯作者：
Kato T
影响因子：
11
作者：
Jia X;Goes FS;Locke AE;Palmer D;Wang W;Cohen-Woods S;Genovese G;Jackson AU;Jiang C;Kvale M;Mullins N;Nguyen H;Pirooznia M;Rivera M;Ruderfer DM;Shen L;Thai K;Zawistowski M;Zhuang Y;Abecasis G;Akil H;Bergen S;Burmeister M;Chapman S;DelaBastide M;Juréus A;Kang HM;Kwok PY;Li JZ;Levy SE;Monson ET;Moran J;Sobell J;Watson S;Willour V;Zöllner S;Adolfsson R;Blackwood D;Boehnke M;Breen G;Corvin A;Craddock N;DiFlorio A;Hultman CM;Landen M;Lewis C;McCarroll SA;Richard McCombie W;McGuffin P;McIntosh A;McQuillin A;Morris D;Myers RM;O'Donovan M;Ophoff R;Boks M;Kahn R;Ouwehand W;Owen M;Pato C;Pato M;Posthuma D;Potash JB;Reif A;Sklar P;Smoller J;Sullivan PF;Vincent J;Walters J;Neale B;Purcell S;Risch N;Schaefer C;Stahl EA;Zandi PP;Scott LJ
通讯作者：
Scott LJ
影响因子：
3.5
作者：
Goryunov, Dmitry;He, Cui-Zhen;Lin, Chyuan-Sheng;Leung, Conrad L.;Liem, Ronald K. H.
通讯作者：
Liem, Ronald K. H.
多功能 Spectraplakin MACF1 的亚型、结构和功能
影响因子：
3.8
作者：
Hu L;Su P;Li R;Yin C;Zhang Y;Shang P;Yang T;Qian A
通讯作者：
Qian A
影响因子：
168.9
作者：
Craddock, Nick;Sklar, Pamela
通讯作者：
Sklar, Pamela